TY - JOUR

T1 - Reducing the Amyloidogenicity of Functional Amyloid Protein FapC Increases Its Ability To Inhibit α-Synuclein Fibrillation

AU - Christensen, Line Friis Bakmann

AU - Jensen, Kirstine Friis

AU - Nielsen, Janni

AU - Vad, Brian Stougaard

AU - Christiansen, Gunna

AU - Otzen, Daniel Erik

PY - 2019/2

Y1 - 2019/2

N2 - Functional amyloid (FA) proteins have evolved to assemble into fibrils with a characteristic cross-β structure, which stabilizes biofilms and contributes to bacterial virulence. Some of the most studied bacterial FAs are the curli protein CsgA, expressed in a wide range of bacteria, and FapC, produced mainly by members of the Pseudomonas genus. Though unrelated, both CsgA and FapC contain imperfect repeats believed to drive the formation of amyloid fibrils. While much is known about CsgA biogenesis and fibrillation, the mechanism of FapC fibrillation remains less explored. Here, we show that removing the three imperfect repeats of FapC (FapC Î"R1R2R3) slows down the fibrillation but does not prevent it. The increased lag phase seen for FapC Î"R1R2R3 allows for disulfide bond formation, which further delays fibrillation. Remarkably, these disulfide-bonded species of FapC Î"R1R2R3 also significantly delay the fibrillation of human α-synuclein, a key protein in Parkinson's disease pathology. This attenuation of α-synuclein fibrillation was not seen for the reduced form of FapC Î"R1R2R3. The results presented here shed light on the FapC fibrillation mechanism and emphasize how unrelated fibrillation systems may share such common fibril formation mechanisms, allowing inhibitors of one fibrillating protein to affect a completely different protein.

AB - Functional amyloid (FA) proteins have evolved to assemble into fibrils with a characteristic cross-β structure, which stabilizes biofilms and contributes to bacterial virulence. Some of the most studied bacterial FAs are the curli protein CsgA, expressed in a wide range of bacteria, and FapC, produced mainly by members of the Pseudomonas genus. Though unrelated, both CsgA and FapC contain imperfect repeats believed to drive the formation of amyloid fibrils. While much is known about CsgA biogenesis and fibrillation, the mechanism of FapC fibrillation remains less explored. Here, we show that removing the three imperfect repeats of FapC (FapC Î"R1R2R3) slows down the fibrillation but does not prevent it. The increased lag phase seen for FapC Î"R1R2R3 allows for disulfide bond formation, which further delays fibrillation. Remarkably, these disulfide-bonded species of FapC Î"R1R2R3 also significantly delay the fibrillation of human α-synuclein, a key protein in Parkinson's disease pathology. This attenuation of α-synuclein fibrillation was not seen for the reduced form of FapC Î"R1R2R3. The results presented here shed light on the FapC fibrillation mechanism and emphasize how unrelated fibrillation systems may share such common fibril formation mechanisms, allowing inhibitors of one fibrillating protein to affect a completely different protein.

KW - AGGREGATION

KW - BIOFILM FORMATION

KW - BIOGENESIS

KW - BRAIN

KW - CLASSIFICATION

KW - CURLI

KW - FILAMENTS

KW - GASTROINTESTINAL-TRACT

KW - INNERVATION

KW - PARKINSONS-DISEASE

UR - http://www.scopus.com/inward/record.url?scp=85062441844&partnerID=8YFLogxK

U2 - 10.1021/acsomega.8b03590

DO - 10.1021/acsomega.8b03590

M3 - Journal article

C2 - 31459612

AN - SCOPUS:85062441844

VL - 4

SP - 4029

EP - 4039

JO - ACS Omega

JF - ACS Omega

SN - 2470-1343

IS - 2

ER -